Polyhydroxyalkanoate medical textiles and fibers

ABSTRACT

Absorbable polyester fibers, braids, and surgical meshes with prolonged strength retention have been developed. These devices are preferably derived from biocompatible copolymers or homopolymers of 4-hydroxybutyrate. These devices provide a wider range of in vivo strength retention properties than are currently available, and could offer additional benefits such as anti-adhesion properties, reduced risks of infection or other post-operative problems resulting from absorption and eventual elimination of the device, and competitive cost. The devices may also be particularly suitable for use in pediatric populations where their absorption should not hinder growth, and provide in all patient populations wound healing with long-term mechanical stability. The devices may additionally be combined with autologous, allogenic and/or xenogenic tissues to provide implants with improved mechanical, biological and handling properties.

This claims priority to U.S. Ser. No. 60/563,096 filed Apr. 16, 2004;U.S. Ser. No. 60/545,771 filed Feb. 19, 2004; U.S. Ser. No. 60/534,065filed Jan. 2, 2004; and U.S. Ser. No. 60/469,469 filed May 8, 2003.

BACKGROUND OF THE INVENTION

The present invention generally relates to textile and fiber-basedmedical devices derived from poly-4-hydroxybutyrate and its copolymers.

Poly-4-hydroxybutyrate (available from Tepha, Inc., Cambridge, Mass. asPHA4400) is a strong pliable thermoplastic that is produced by afermentation process (see U.S. Pat. No. 6,548,569 to Williams et al.).Despite its biosynthetic route, the structure of the polyester isrelatively simple (FIG. 1). The polymer belongs to a larger class ofmaterials called polyhydroxyalkanoates (PHAs) that are produced bynumerous microorganisms, Steinbüchel, A. Polyhydroxyalkanoic acids,Biomaterials, 123-213 (1991); Steinbüchel A., et al. Diversity ofBacterial Polyhydroxyalkanoic Acids, FEMS Microbial. Lett. 128:219-228(1995); and Doi, Y. Microbial Polyesters (1990). In nature thesepolyesters are produced as storage granules inside cells, and serve toregulate energy metabolism. They are also of commercial interest becauseof their thermoplastic properties, and relative ease of production.Several biosynthetic routes are currently known to producepoly-4-hydroxybutyrate, as shown in FIG. 2. Chemical synthesis ofpoly-4-hydroxybutyrate has been attempted, but it has been impossible toproduce the polymer with a sufficiently high molecular weight necessaryfor most applications, Hori, Y., et al. Chemical Synthesis of HighMolecular Weight poly(3-hydroxybutyrate-co-4-hydroxybutyrate, Polymer36:4703-4705 (1995).

Tepha, Inc. (Cambridge, Mass.) produces PHA4400 and related copolymersfor medical use, and has filed a Device Master Files with the UnitedStates Food and Drug Administration (FDA) for PHA4400. Relatedcopolymers include 4-hydroxybutyrate copolymerized with3-hydroxybutyrate or glycolic acid (U.S. Ser. No. 60/379,583 to Martin &Skraly, U.S. Pat. No. 6,316,262 to Huisman et al., and U.S. Pat. No.6,323,010 to Skraly et al.). Tepha has also filed a Device Master Filewith the United States FDA for copolymers containing 3-hydroxybutyrateand 4-hydroxybutyrate. Methods to control molecular weight of PHApolymers have been disclosed by U.S. Pat. No. 5,811,272 to Snell et al.,and methods to purify PHA polymers for medical use have been disclosedby U.S. Pat. No. 6,245,537 to Williams et al. PHAs with degradationrates in vivo of less than one year have been disclosed by U.S. Pat. No.6,548,569 to Williams et al. and PCT WO 99/32536 to Martin et al. Theuse of PHAs as tissue engineering scaffolds has also been disclosed byU.S. Pat. No. 6,514,515 to Williams, and other applications of PHAs havebeen reviewed in Williams, S. F., et al. Applications of PHAs inMedicine and Pharmacy, in Biopolymers, Polyesters, III Vol. 4:91-127(2002).

In the practice of surgery there currently exists a need for absorbablefibers and surgical meshes with improved performance. For example, thereis currently a need for an absorbable monofilament fiber with aprolonged strength retention that can be used as a suture material. Sucha product would potentially be useful in the treatment of patients withdiabetes, obesity, nutritional impairment, compromised immune systems,or other conditions such as malignancy or infection that compromisewound healing.

There also exists a need for improved surgical meshes. For example, anabsorbable hernia mesh with prolonged strength retention could have manyadvantages over the non-absorbable synthetic meshes currently used inhernia operations (Klinge, U., et al., Functional Assessment and TissueResponse of Short- and Long-term Absorbable Surgical Meshes,Biomaterials 22:1415-1424 (2001). Long-term implantation of thesenon-absorbable meshes is not considered ideal because they can lead tocomplications such as adhesions (fistula formation), pain, andrestriction of physical capabilities (Klinge et al., 2001). If implantedinto surgical sites that are contaminated or have the potential tobecome contaminated, 50-90% of these non-absorbable implants will needto be removed (Dayton et al. 1986). These implants are also not idealfor use in pediatric patients where they could hinder growth (Klinge etal., 2001). To date, the use of absorbable synthetic surgical meshes inhernia repair has been found to almost invariably result in largeincisional hernias that require revision operations because of therelatively short-term strength retention of these materials (Klinge etal., 2001). However, it is thought that an absorbable hernia mesh withprolonged strength retention could solve this problem providing amechanically stable closure, reduce the incidence of adhesions and risksof infection, and be suitable for use in pediatric patients.

In addition to the need for improved meshes for hernia repair, there arealso needs for improved meshes and patches for other procedures. Inpericardial repair there exists a need for a surgical material that willprevent adhesions between the sternum and heart following open-heartsurgery. There are also similar needs to prevent adhesions in spinal andgynecology procedures that could be addressed with improved surgicalmeshes and patches.

Biomaterial patches derived from animal and human tissue are currentlyused fairly extensively in cosmetic surgery, cardiovascular surgery,general surgery (including hernia repair), and in urology and gynecologyprocedures for the treatment of conditions that include vaginal prolapseand urinary incontinence. There is however reported to be growingconcern about the use of animal and human derived biomaterials becauseof the risks associated with disease transmission. Synthetic absorbablemeshes and patches that may offer decreased risks of diseasetransmission are currently limited, can be inflammatory, and do notprovide prolonged strength retention. Thus there currently exists a needto develop new absorbable meshes for these procedures as well. Ideally,these products should have prolonged strength retention, induce minimalinflammatory responses that resolve, provide mechanically stablereinforcement or closure, offer anti-adhesion properties (wherenecessary), minimize the risks of disease transmission, and afterabsorption leave a healthy natural tissue structure.

There is thus a need to develop absorbable fibers with prolongedstrength retention that could be used as suturing materials, or insurgical meshes. The latter, offering longer-term mechanical stability,could also be used in other procedures such as pelvic floorreconstruction, urethral suspension (to prevent stress incontinenceusing the mesh as a sling), pericardial repair, cardiovascular patching,cardiac support (as a sock that fits over the heart to providereinforcement), organ salvage, elevation of the small bowel duringradiation of the colon in colorectal cancer patients, retentive devicesfor bone graft or cartilage, guided tissue regeneration, vasculargrafting, dural substitution, nerve guide repair, as well as inprocedures needing anti-adhesion membranes and tissue engineeringscaffolds. Strong absorbable fibers could also find other uses, forexample, in synthetic ligament and tendon devices or scaffolds. Furtheruses include combinations with other synthetic and natural fibers,meshes and patches. For example, the absorbable fibers and devices suchas meshes and tubes derived from the fibers could be combined withautologous tissue, allogenic tissue, and/or xenogenic tissues to providereinforcement, strengthening and/or stiffening of the tissue. Suchcombinations could facilitate implantation of the autologous, allogenicand/or xenogenic tissues, as well as provide improved mechanical andbiological properties. Combination devices could be used for example inhernia repair, mastopexy/breast reconstruction, rotator cuff repair,vascular grafting/fistulae, tissue flaps, pericardial patching, tissueheart valve implants, bowel interposition, and dura patching.

It is therefore an object of this invention to provide absorbablefibers, surgical meshes, and medical devices with one or more of thefollowing features: prolonged strength retention in vivo, anti-adhesionproperties, minimal inflammatory reaction upon implantation, minimalrisk for disease transmission or to potentiate infection, remodeling invivo to a healthy natural tissue.

It is another object of this invention to provide methods forfabricating the articles and devices with prolonged strength retention.

It is yet another object of the invention to provide absorbablemultifilament fibers, and methods for fabricating these multifilamentsinto surgical meshes.

It is still yet another object of the invention to combine the fibersand meshes with autologous, allogenic and/or xenogenic tissues toprovide improved mechanical, biological and handling properties of theautologous, allogenic and/or xenogenic tissues.

SUMMARY OF THE INVENTION

Absorbable polyester fibers, braids, and surgical meshes with prolongedstrength retention have been developed. These devices are preferablyderived from biocompatible copolymers or homopolymers of4-hydroxybutyrate. These devices provide a wider range of in vivostrength retention properties than are currently available, and offeradditional benefits such as anti-adhesion properties, reduced risks ofinfection or other post-operative problems resulting from absorption andeventual elimination of the device, and competitive cost.

The devices are also particularly suitable for use in pediatricpopulations where their absorption should not hinder growth, and providein all patient populations wound healing with long-term mechanicalstability. The devices may additionally be combined with autologous,allogenic and/or xenogenic tissues to provide implants with improvedmechanical, biological and handling properties.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is the chemical structure of poly-4-hydroxybutyrate (P4HB,poly-4-hydroxybutyrate).

FIG. 2 shows some of the known biosynthetic pathways for the productionof P4HB. Pathway enzymes are: 1. Succinic semialdehyde dehydrogenase, 2.4-hydroxybutyrate dehydrogenase, 3. diol oxidoreductase, 4. aldehydedehydrogenase, 5. Coenzyme A transferase and 6. PHA synthetase.

FIG. 3 is a graph of strength retention data of PHA4400 fibers (in vitroand in vivo) compared with PDS control fiber (in vivo).

FIG. 4 is a graph comparing the tensile mechanical properties of PHA4400and commercially available monofilament sutures.

FIG. 5 is a graph of the degradation of PHA4400 (P4HB) samples in vivocompared to in vitro controls. The Mw for implanted (in vivo) and buffercontrol sutures (in vitro) is plotted versus time.

FIG. 6 is a graph of the ratio of mass and length of the PHA4400 sutures(in vitro and in vivo) plotted as a function of degradation time.

DETAILED DESCRIPTION OF THE INVENTION

Absorbable fibers and meshes with prolonged strength retention have beendeveloped.

I. DEFINITION

Strength retention refers to the amount of time that a materialmaintains a particular mechanical property following implantation into ahuman or animal. For example, if the tensile strength of an absorbablefiber decreased by half over 3 months when implanted into an animal, thefiber's strength retention at 3 months would be 50%.

Biocompatible refers to the biological response to the material ordevice being appropriate for the device's intended application in vivo.Any metabolites of these materials should also be biocompatible.

Poly-4-hydroxybutyrate means a homopolymer comprising 4-hydroxybutyrateunits. It may be referred to as P4HB, PHA4400 or TephaFLEX™ biomaterialand is manufactured by Tepha Inc., Cambridge, Mass.

Copolymers of poly-4-hydroxybutyrate mean any polymer comprising4-hydroxybutyrate with one or more different hydroxy acid units.

II. SOURCE OF POLY-4-HYDROXYBUTYRATE AND COPOLYMERS THEREOF

Tepha, Inc. of Cambridge, Mass. produces poly-4-hydroxybutyrate andcopolymers thereof using transgenic fermentation methods.

III. POLY-4-HYDROXYBUTYRATE FIBERS WITH PROLONGED STRENGTH RETENTION

Around 1984, a division of Johnson and Johnson (Ethicon) firstintroduced a monofilament synthetic absorbable suture known as PDS™,made from polydioxanone. This suture retains about 50% of its strengthup to 6 weeks after implantation, and is completely absorbed in the bodywithin 6 months. Davis and Geck subsequently introduced a monofilamentsuture based on a copolymer of glycolide and trimethylene carbonate thatis sold under the tradename of Maxon™. This suture has a similarstrength retention to PDS™. Two other monofilament sutures wereintroduced more recently. Monocryl™ based on segmented copolymers ofglycolide and caprolactone, and Biosyn™ based on a terpolymer ofglycolide, p-dioxanone, and trimethylene carbonate. Monocryl™ isreported to have a 20-30% breaking strength after 2-3 weeks, and becompletely absorbed after 3-4 months. Biosyn™ has an absorption profilesimilar to Monocryl™. Despite continued innovation in the development ofabsorbable synthetic monofilament sutures there is still a need for asynthetic absorbable suture with extended strength retention forpatients requiring long-term wound support, for example, a monofilamentsuture with 50% strength retention at 3-6 months (after implantation).There are also limited options for synthetic absorbable meshes withprolonged strength retention.

U.S. Pat. No. 6,548,569 to Williams et al. discloses thatpoly-4-hydroxybutyrate has a slower absorption rate in vivo than manymaterials used as absorbable sutures, and provides absorption data forunoriented poly-4-hydroxybutyrate films and porous samples. It does not,however, disclose the strength retention of fibers ofpoly-4-hydroxybutyrate following implantation.

It has now been discovered that oriented fibers of PHA4400 andcopolymers thereof can be prepared with tensile strengths comparable toexisting synthetic absorbable suture fibers (such as PDS™), but have aprolonged strength retention in vivo of over 20-30% at 3-6 months. Incomparison, a control PDS suture had little tensile strength remainingafter 12-15 weeks.

It has also been discovered that oriented poly-4-hydroxybutyrate fiberscan be used to prepare surgical meshes and tubes with prolonged strengthretention. These fiber and textile devices may further be combined withautologous, allogenic and/or xenogenic tissues to impart improvedproperties to these implantable tissues. Properties that can be improvedthrough this combination include mechanical properties such as tensilestrength and modulus, for example, to reinforce the tissues to make themstronger, stiffer, more durable, and easier to implant.

Non-limiting examples are given herein to describe the methods forpreparing the fibers, meshes, and composite devices with autologous,allogenic and/or xenogenic tissues, and to illustrate the strengthretention of the fibers upon implantation.

Example 1 Melt Extrusion of PHA4400 to Produce Monofilament Fibers

PHA4400 (Tepha, Inc., Cambridge, Mass.) (Mw 575K) was ground into smallpieces using a Fritsch cutting mill (Pulversette 15, 10 mm bottom sieve)and dried under vacuum overnight prior to melt processing. Monofilamentfibers of PHA4400 were melt extruded using an AJA (Alex JamesAssociates, Greer, S.C.) ¾″ single screw extruder (24:1 L:D, 3:1compression) equipped with a Zenith type metering pump (0.16 cc/rev) anda die with a single hole spinnerette (0.026″, 2:1 L:D). The 4 heatingzones of the extruder were set at 140°, 190°, 200° and 205° C. Theextruder was set up with a 15 ft drop zone, 48″ air quench zone (10°C.), a guide roll, three winders and a pickup. The fiber was orientedin-line with extrusion by drawing it in a multi-stage process to providefiber with high tensile strength and a reduced extension to break. Thefiber was drawn in-line to stretch ratios of 6 to 11×. A spin finish(Goulston, Lurol PT-6A) was dissolved in iso-propanol at 10 vol/vol %and applied to the fiber before the first roll to act as a lubricant andprotect the fiber during downstream processing. A series of fibers ofdifferent sizes were produced by varying the extrusion conditions(metering pump speed) and drawing conditions (draw ratio). Tensilemechanical properties of the melt extruded fibers were determined usinga universal mechanical tester, and results are shown in Table 1. As isevident, the tensile strength of the oriented PHA4400 fiber iscomparable to 450-560 MPa reported for the commercial suture fiber,PDS™, Chu, C. C., et al. Wound Closure Biomaterials and Devices, CRCPress (1997). The weight average molecular weight (Mw) of the fibers wasdetermined by gel permeation chromatography (GPC) and is also shown inTable 1.

TABLE 1 Properties of melt extruded PHA4400 monofilament. TensileElongation Draw Diameter Load at Strength to Break Mw** Sample Ratio(μm) break (g) (MPa) (%) (K) 1 5.95 125 533 426 107 338 2 5.95 113 274268 126 293 3 5.95 82 68 126 34 278 4 5.95 128 389 297 134 302 5 6.00134 426 296 118 313 6 10.75 120 569 494 32 348 7 10.75 120 446 387 29356 10* 10.75 217 1304 346 70 395 11* 5.95 190 1291 447 135 396 *Note:Samples 10 and 11 were spun through a larger spinnerette (0.045″, 2:1L:D). **Note Mw of starting polymer was 575 K.

Example 2 Strength Retention and Biocompatibility of PHA4400Monofilament Fibers

An implantation study to determine the strength retention of PHA4400fibers was undertaken in a rabbit model. Sample 10 (shown in Table 1)was selected for these studies because the fiber had an elongation tobreak of 70% and tensile strength of 346 MPa (60,000 psi) that iscomparable to commercial monofilament absorbable sutures. Prior toimplantation the fiber was sterilized using cold ethylene oxide gas (40°C., ethylene oxide pressure of 13.7 INHGA, humidity of 1.7 INHGA, dwelltime 4 hr, and aeration time 10 hr). A small amount of fiber shrinkage(2%) was noted to result during the sterilization process. A commercialmonofilament absorbable suture material, PDS™, was used as a control.

Under sterile conditions, the sterilized sutures were placedperpendicular to the dorsal midline of the rabbit. After making a smallincision, a large hemostat was introduced through the incision into thesubcutaneous tissue and tunneled approximately 9 inches into thesubcutis layer. The PHA4400 and control (3/0 PDS™) suture fibers werethreaded individually through separate surgically created implant areasand left in place. The incisions were closed with tissue glue. A totalof four test and four control samples were implanted in each rabbit.Animals were maintained for periods of 1, 4, 8, 12, 16 and 26 weeks (2rabbits per time point) and were observed daily to ensure proper healingof the implant sites. At the end of the appropriate time points, theanimals were weighed and euthanized by an injectable barbituate. Tissuesections containing the implanted sutures were excised from the animals.One test and one control sample were fixed in formalin and retained forhistological analysis of the tissue surrounding the suture implants. Theremaining three samples from each group were cleaned of tissue, wrappedin sterile, saline soaked gauze and returned on the day of explantationfor further analysis. Suture samples were further cleaned of residualtissue and dried.

In parallel with the in vivo degradation study, an in vitro degradationstudy was conducted to generate comparative data. Sterilized PHA4400monofilament fibers, identical with those used in the implantationstudy, were incubated in Dulbeco's phosphate buffered saline (pH 7.4,37° C.) containing sodium azide (0.05%) as a preservative. Six controlPHA4400 sutures per time point were enclosed in sterile polyethylenesample bags and removed at the same time as each of the implant samples.The in vivo and in vitro samples were processed identically.

Strength Retention

The explanted suture samples were subject to tensile testing accordingto the procedure of ASTM D2256-97. The results of this tensile testingare shown in FIG. 3. As can be seen, the PHA4400 and PDS™ controlsutures had very comparable starting tensile strengths (60,000 psi). Asexpected, the PDS™ control sutures maintained 50% of their initialtensile strength until approximately the 6^(th) week. In contrast, theimplanted PHA4400 sutures retained approximately 30% of their tensilestrength through the 26^(th) week. A comparison of the tensilemechanical properties of PHA4400 and commercially available monofilamentsutures is shown in FIG. 4.

Unlike the implanted suture, the PHA4400 in vitro control suture showeda more gradual loss of strength during the entire 26-week degradationstudy, retaining 80% of its original strength. This result demonstratesthe mechanical stability of the polymeric material to simple hydrolysis.

Molecular Weight and Mass Loss

In addition to the strength retention of the PHA4400 suture fibers, theMw of the PHA4400 samples were analyzed by GPC. As shown in FIG. 5, theMw of the implanted and control PHA4400 sutures decreased graduallyduring the course of the degradation study to approximately 43% of theiroriginal Mw at 26 weeks. Additionally, there does not appear to be asignificant difference between the Mw of the implanted and the in vitrocontrol PHA4400 sutures. This result shows that the hydrolytic stabilityof the implanted sample is very similar to the in vitro control.

In order to determine the mass loss of the samples over time, the massand length of the PHA4400 sutures (in vitro and in vivo) were determinedand plotted as a function of degradation time. The ratio of mass tolength of the PHA4400 samples (implanted and buffer control) is plottedvs. degradation time and shown in FIG. 6. The mass/length ratio wasdetermined rather than just the mass of the sample, because this rationormalizes for samples that were cut during implantation or that breakduring harvest. As can be seen in this figure, the implanted suturesappear to loose mass more rapidly than the in vitro controls. This datashows that the implanted samples lost mass more rapidly than the invitro control samples and suggests that surface degradation is occurringin vivo.

Tissue Reaction

The tissue surrounding the implanted PHA4400 and PDS™ control sutureswas analyzed for the tissue reaction to the implanted articles throughthe 26-week time point. Formalin fixed tissue samples (PHA4400 and PDS™control) from each test animal were sectioned and graded by a boardcertified veterinarian for the following: inflammation, fibrosis,hemorrhage, necrosis, degeneration, foreign debris and relative size ofinvolved area.

Hisotopathological evaluation indicated that the finding at the PDS™control and PHA4400 sites were similar and there were no significantindications of a local toxic effect in either the control or the testsites.

Example 3 Knitted Mesh of PHA4400 Monofilament Fibers with ProlongedStrength Retention

A warp knitted mesh of PHA4400 was produced from 100 μm diameteroriented monofilament PHA4400 fiber produced as described in Example 1.A warp knit type of construction is desirable as an implant because itcan be cut by the surgeon and will not readily unravel. The mesh wasfabricated using fiber of 100 μm monofilament PHA4400, tensile strength92,000 psi, and an elongation to break of 77%. Fabric construction wasas follows: Mach #30 Raschel Knit 36 gauge fabric, 150 ends, 16 courses,40 stitches per inch, using 18 needles per inch. Specifications for thefinished fabric were: Weight: 58 g/m² (1.72 oz/sq. yard), Thickness:0.29 mm.

Example 4 Extrusion of Suture Fibers of a Copolymer of Glycolate and4-hydroxybutyrate (PHA4422)

PHA4422 containing 5% glycolic acid comonomer (Mw 305,000 by GPC) wasmelt extruded into a fiber and converted to a suture as follows. Thepolymer was prepared by milling the bulk polymer into approximately 1 mmsized particles using a P-15 laboratory cutting mill (Fritsch, Germany)dried in a vacuum desicator. The polymer was extruded using an AJA ⅝″single screw extruder (Alex James and Associates) with a single-holespinneret (0.040″, 2:1 L/D). The extruder had five separate temperaturezones that were set to 120, 154, 155, 160 and 160° C. from the inlet tothe outlet, with a gear pump at the outlet. The total residence time inthe extruder was estimated at 9 minutes.

After extrusion there was a 10 ft drop zone through air before aquenching water bath (5° C.). Following the quench bath, three winderswere used to collect the fiber. A first winder was set for a speed ofabout 2.5 meters per minute. The bath length was about 3-4 ft and theresidence time for the fiber in the bath was estimated at about 30seconds. Crystallization of the fiber occurred before the first winder.Two additional winders (17.5 and 19.5 meters/minute) extended the fiberabout 8 times (8× draw). A take up unit was used with only slighttension. Varying the polymer extrusion rate while keeping the downstreamorientation and take up rates the same produced fibers of differentdiameters. Initially, the extruder was set at a gear pump rate of 7, andthen successively slowed resulting in fibers of approximately 375, 275and 200 μm diameter, see Table 2.

Suture needles were attached to each of the different diameter fibersand the sutures were packaged for sterilization. Tensile strength(straight and knot pull) was determined for representative samples ofthe sutures, see Table 2.

TABLE 2 Physical characterization of sutures prepared by melt extrusionof PHA4422 (5% glycolic acid comonomer, Mw 300K). Fiber CorrespondingTensile Strength Elongation Tensile Strength Elongation diameter USPsize Straight Pull Straight Pull Knot Pull Knot Pull (μm) approx. (lbf)(%) (lbf) (in) 375 +/− 6 0 9.2 +/− 1.6 128 +/− 33 4.6 +/− 0.4  51 +/−4.2 256 +/− 1 2/0 5.3 +/− 0.3  65 +/− 13 3.8 +/− 0.8 49 +/− 18 199 +/− 54/0 3.0 +/− 0.3 130 +/− 24 1.6 +/− 0.3 44 +/− 15

Example 5 Monofilament Fiber with Peak Tensile Stress of Greater that 70kg/mm²

Melt spinning of Poly-4-hydroxybutyrate “PHA4400” polymer has beenextremely difficult to accomplish due to melt flow instability andtackiness of resulting fiber. Melt leaving the spinning die exhibitedperiodic diameter fluctuation and helical structure. These flowirregularities are known as melt fracture or “elastic turbulence” andare generated while the melt is entering and passing through spinnerethole. The reason for such flow irregularities is very high viscosity ofthe viscoelastic melt and a very high elastic function at the exitingpoint of spinneret capillary.

The low glass transition temperature of about −50° C., and the lowtendency to crystallize of this polymer explain the stickiness of thefibers. In addition to that, the orientation, which was generated duringmelt spinning, relaxed after a very short time so that the fibersoffered a low tenacity for further drawing.

This example illustrates our ability to overcome the above processingproblems and produce high strength fiber. PHA4400 polymer was dried toless than 0.01% moisture. Dried pellets of the PHA4400 were fed to anextruder barrel under a blanket of nitrogen. Barrel temperatures zoneswere kept at 100° C. feed, 150° C. transition and 200° C. metering.Molten polymer passed through a heated block to a metering pump thenextruded from a die with a single hole spinneret. The block, meteringpump and the die were kept at 220° C. temperature. Pump dischargepressure was kept below 1000 psi by control of temperatures, and thespeed of the metering pump. Spun extrudate filament was free from allmelt irregularities. The extrudate was allowed dwell time to crystallizeafter which further multi stage drawing was possible to increase crystalorientation and gain strength. The fiber was then heat treated androlled on a winding spool. Properties of the ensuing fiber are shown inTable 3.

TABLE 3 Physical characterization of fibers prepared by melt spinning ofPHA4400 Fiber Fiber Peak Min Break Min Break Min Break Min Diam. MaxDiam. Load Strength Strength Strength microns microns kgfkgf/mm{circumflex over ( )}2 PSI MPa 0.070 0.089 0.46 73.98 1.05E+05 7260.129 0.178 1.80 72.37 1.03E+05 710 0.256 0.305 5.50 75.32 1.07E+05 7390.421 0.470 13.00 74.97 1.07E+05 735 0.523 0.622 22.70 74.74 1.06E+05733 “Diam” means Diameter

Example 6 Monofilament Fibers with Prolonged In Vivo Strength Retention

The PHA4400 monofilaments prepared as in Example 5 were sterilized usingcold ethylene oxide gas (40° C., ethylene oxide pressure of 13.7 INHGA,humidity of 1.7 INHGA, dwell time 4 hr, and aeration time 10 hr).

Under sterile conditions, the sterilized monofilament fibers were placedperpendicular to the dorsal midline of the rabbit. After making a smallincision, a large hemostat was introduced through the incision into thesubcutaneous tissue and tunneled approximately 9 inches into thesubcutis layer. The PHA4400 fibers were threaded individually throughseparate surgically created implant areas and left in place. A total offour test and four control samples were implanted in each rabbit.Animals were maintained for a period of 2 weeks (2 rabbits) and wereobserved daily to ensure proper healing of the implant sites. At the endof the appropriate time points, the animals were weighed and euthanized.Tissue sections containing the implanted sutures were excised from theanimals. Samples were cleaned of tissue, wrapped in sterile, salinesoaked gauze and returned on the day of explantation for furtheranalysis. Suture samples were further cleaned of residual tissue anddried. Tensile strength was determined on a universal testing machine.The tensile breaking load of the explanted fiber after 2 weeksimplantation was found to be 8.5 lbf peak load, which is 87% of that ofthe starting fiber (9.8 lbf). Thus these fibers demonstrated a higherstrength retention in vivo (87% at 2 weeks) when compared to the fibersin Example 2, FIG. 3 (50% at 2 weeks).

Example 7 Multifilament Yarn

Fiber spinning was carried out in the same manner as example 5 exceptwith the die having a multi hole spinneret (20 holes×0.0065 inches).Extrudate yarn was allowed time to crystallize, and a super cooledstream of gaseous media/liquid mist perpendicular to the fiber axis wasintroduced. A subzero bath was also used and proved a suitablesubstitute for the gaseous media. The resulting filaments were furtherprocessed through cold and heated godets, and the filaments could beoriented and heat set. Yarn tenacity of greater than 3.5 gpd (gram perdenier) with 30% elongation was obtained. Representative data for themultifilament yarns is shown in Table 4.

TABLE 4 Tensile properties for PHA4400 multifilament yarns. Denier perPeak Load Strain at Tenacity Sample filament Kg break (%) g/denier 133.8 2.43 97 3.6 2 27.1 1.69 114 3.1 3 23.7 1.92 58 4.1 4 16.2 1.12 1133.4 5 12.8 0.99 107 3.9 6 10.3 0.71 74 3.5

Example 8 Knitted Fabric from a Multifilament Yarn

A multifilament yarn was knitted into a tube using a single feed,circular weft knitting machine (Lamb Knitting Co., model ST3A/ZA). Thewidth of the flat tube was approximately 9 mm. The yarn knitted verywell without evidence of fiber breakage even without the addition of aspin finish as a lubricant. After cleaning and sterilization, theknitted tube appears well suited for use as an absorbable medicalfabric.

Example 9 Absorbable Polymeric Support Structure for Biological TissueImplant

PHA4400 fiber woven, knitted or braided into semi rigid support tubes orPHA4400 polymer directly extruded into support tubes can be preparedwith an inner diameter closely matching that of a biological substrateimplant (e.g. autologous, allogenic and/or xenogenic tissue). Thebiological implant can be inserted into the support tube, and mayoptionally be secured in place, for example, by suturing, prior toimplantation. The addition of the support tube provides improvedstrength, modulus, and can make implantation easier. Similarly sheets ofextruded film, woven, non-woven or knitted fabric may be rolled over abiological tissue implant and the fabric ends may be tied, sutured orglued to maintain a semi-rigid construct over the biological implant.

A woven tube was produced from 0.300 mm diameter monofilament PHA4400fiber extruded as described in Example 5. Using circular weavingequipment a 10 mm inside diameter tube was produced. The tubeconstruction allowed insertion of an implant biological substrate andprovided enough stiffness to position and suture an otherwise flaccidbiological implant.

1. A fiber comprising poly-4-hydroxybutyrate polymer wherein the fiberhas a tensile strength of greater than 126 MPa.
 2. The fiber of claim 1wherein the weight average molecular weight of the fiber decreases lessthan 80% after implantation for 6 months.
 3. The fiber of claim 1wherein the weight average molecular weight of the fiber decreases lessthan 75% after implantation for 2 weeks.
 4. The fiber of claim 1 whereinthe tensile strength of the fiber decreases less than 80% afterimplantation for 6 months.
 5. The fiber of claim 1 wherein the tensilestrength of the fiber decreases less than 75% after implantation for 2weeks.
 6. The fiber of claim 1 wherein the elongation to break is over20%.
 7. The fiber of claim 1 wherein the polymer is a copolymercontaining 4-hydroxybutyrate and one or more co-monomers.
 8. The fiberof claim 7 wherein the co-monomer is glycolate.
 9. The fiber of claim 7wherein the co-monomer is 3-hydroxybutyrate.
 10. The fiber of claim 1wherein the fiber is a monofilament, multifilament, or braidedstructure.
 11. The fiber of claim 1 wherein the fibers of the polymerhave been oriented.
 12. A device comprising one or more fiberscomprising poly-4-hydroxybutyrate polymer having a tensile strength ofgreater than 126 MPa selected from the group consisting of a medicaltextile, tube, general surgical mesh, hernia mesh, pericardial patch,anti-adhesion patch, cardiovascular patch, guided tissue regenerationpatch, sling, monofilament suture, multifilament suture, braid,ligament, tendon, meniscus repair device, cartilage repair device, nerveguide, stent, vascular graft, and dura.
 13. The device of claim 12wherein the device is a knitted mesh, woven mesh, or nonwoven mesh. 14.The device of claim 12 wherein the weight average molecular weight ofthe fiber in the device decreases less than 80% after implantation for 6months.
 15. The device of claim 12 wherein the weight average molecularweight of the fiber in the device decreases less than 75% afterimplantation for 2 weeks.
 16. The device of claim 12 wherein the tensilestrength of the fiber in the device decreases less than 80% afterimplantation for 6 months.
 17. The device of claim 12 wherein thetensile strength of the fiber in the device decreases less than 50%after implantation for 2 weeks.
 18. The device of claim 12 wherein thebreaking strength of the device is at least 10 psi. 19-20. (canceled)21. A device selected from the group consisting of a medical textile,tube, general surgical mesh, hernia mesh, pericardial patch,anti-adhesion patch, cardiovascular patch, guided tissue regenerationpatch, sling, monofilament suture, multifilament suture, braid,ligament, tendon, meniscus repair device, cartilage repair device, nerveguide, stent, vascular graft, and dura, the device comprising one ormore fibers comprising poly-4-hydroxybutyrate polymer wherein the fiberhas a tensile strength of greater than 126 MPa.
 22. The device of claim21 further comprising harvested autologous tissue, allogenic tissue, orxenogenic tissue.
 23. The device of claim 22 wherein the devicereinforces, supports, strengthens, or stiffens the autologous,allogenic, and/or xenogenic tissues.
 24. The device of claim 23 whereinthe device stiffens the tissue to facilitate implantation.
 25. Thedevice of claim 22 wherein the harvested autologous tissue, allogenictissue, or xenogenic tissues is selected from the group consisting ofvascular grafts, heart valves, pericardium, skin, intestine, muscle,ligament and tendon, cartilage and meniscus, nerves, dura, fascia, andorgans. 26-31. (canceled)